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Impact de la protéine SHP2 associé au syndrome de Noonan sur le métabolisme glucidique

Abstract : Type 2 diabetes (T2D) is a disease that affects more and more people worldwide and has many severe, lifethreatening complications. The current therapies are rather limited, because even if they are effective, they are associated with significant side effects. Thus, it is important to find new therapeutic targets to improve insulin sensitivity in obesity or diabetes. We are interested here in a new potential target called SHP2, a protein tyrosine phosphatase involved in signal transduction by regulating several canonical pathways (MAPK, PI3K). This protein is known for its crucial roles in development as well as its involvement in glucidic metabolism. However, this latter function is still poorly understood because the effect of a deletion of SHP2 on insulin sensitivity is different between tissues and its overall role is not known. Here, to study the impact of SHP2 on whole body glucidic metabolism we used Noonan Syndrome (NS) as an original model system. Indeed, this genetic disease is mainly caused by a hyperactivating mutation of the gene PTPN11 encoding the protein SHP2. The study of glucidic metabolism in the context of SN has revealed glucose intolerance, which is dissociated from reduced adiposity, both in patients and in the murine model of the disease (SHP2D61G/+). We show that NS mice exhibit inflammation characterized by overexpression of pro-inflammatory markers, as well as an increase of pro-inflammatory macrophages in metabolic tissues. Thanks to bone marrow transplantation and clodronate treatment, we show this inflammation comes from macrophage and is the cause of the insulin resistance in SN.[...]
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Submitted on : Wednesday, November 27, 2019 - 3:22:10 PM
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Romain Paccoud. Impact de la protéine SHP2 associé au syndrome de Noonan sur le métabolisme glucidique. Médecine humaine et pathologie. Université Paul Sabatier - Toulouse III, 2018. Français. ⟨NNT : 2018TOU30242⟩. ⟨tel-02381678v2⟩

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